Diisopropylethylamine → (S)-[2-{-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol]

HRID 1593123노트

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HRID 1593123 반응식
[C:1]1([C:7](=[O:15])[CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:27](O)=O)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CN([P+](Br)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(Cl)Cl.O.CCOCC.C1COCC1.CCOC(C)=O.CCCCCC>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([CH2:27][N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[OH:15])[CH2:10]3)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1

참가 물질

11

반응물 5

HCID 81531DiisopropylethylamineHCID 6027611-(p-Chlorophenyl)cyclobutanecarboxylic acidHCID 10221847Bromotris(dimethylamino)phosphonium HexafluorophosphateHCID 21226445Aluminium lithium hydrideHCID 68645108(S)-[1-Phenyl-2-piperidin-3-yl-ethanone]

생성물 1

HCID 68644572(S)-[2-{-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol]수율 76.3%

시약·촉매·용매 5

HCID 962Water용매HCID 3283Diethyl Ether용매HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매HCID 21226206Ethyl acetate hexane용매

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온도
0 °C

실험 절차

(S)-[1-Phenyl-2-piperidin-3-yl-ethanone] (142 mg, 0.70 mmol) and 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid (148 mg, 0.70 mmol) were dissolved in 5 mL of methylene chloride and treated with the amide coupling agent BROP (1.05 mmol), and diisopropylethylamine (2.1 mmol). The mixture was kept at room temperature overnight, diluted with 20 mL of water, and 50 mL of ether. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired amide intermediate 2-{1-[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-piperidin-3-yl}-1-phenyl-ethanone (254 mg, 92%). This amide was dissolved in 10 mL of THF at 0° C. and excess lithium aluminum hydride (245 mg) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 1.5 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 205 mg of (S)-[2-{1-[1-(4-Chloro-phenyl)-cyclobutylmethyl]-piperidin-3-yl}-1-phenyl-ethanol], 182, was obtained (83%). 1H and 13C NMR data was consistent with the assigned structure. Data for this compound as a mixture of diastereomers: MS 384 (M++1).

후처리

  1. customExtractive workup gave
  2. temperatureThe solution was heated
  3. temperatureto reflux for 5 minutes
  4. customquenched by dropwise addition of 1.5 mL 1M NaOH
  5. additionAdditional THF (10 mL) was added
  6. filtrationfiltered though a plug of sodium sulfate
  7. customThe solution thus obtained
  8. concentrationwas concentrated in vacuo
  9. customthe residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide

출처 및 근거

ORD 기록
ord-5018c3317a204f51b2eb8f6485908e20
출처 데이터셋
uspto-grants-2007_11
특허 번호
US07294637B2

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